Topical phytotherapeutic compound for the treatment of herpes based on uncaria tomentosa and extraction process for obtaining a vegetal extract from uncaria tomentosa

ABSTRACT

The present invention concerns a phytotherapic compound for the treatment of herpes based on  Uncaria tomentosa  characterized by the presence of: (a) A therapeutically efficient amount of an Herbal Extract from  Uncaria tomentosa  (Willd) DC Rubiaceae, (b) a pharmaceutically acceptable vehicle, (c) at least one pharmaceutically acceptable excipient, and, (d) optionally, pharmaceutically acceptable adjuvants. It also concerns a process of extraction for obtaining the Herbal Extract from  Uncaria tomentosa  (Willd) DC Rubiaceae, active ingredient of the phytotherapic compound for the treatment of herpes of the present invention.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. application Ser. No.11/661,599, filed Mar. 1, 2007, which is incorporated herein byreference.

FIELD OF THE INVENTION

The present invention concerns a topical phytotherapic compound, basedon an Uncaria spp extract, designed for the treatment of mucocutaneousHerpes simplex.

BACKGROUND OF THE INVENTION

The use of topical products in the treatment of the mucocutaneous Herpessimplex in immunocompetent patients is currently restricted to theutilization of antiviral drugs which inhibit the DNA polymerase in thecells infected by the virus, preventing its replication. Among theaforementioned antiviral drugs, the most important is the acyclovirfamily (pencyclovir, gancyclovir, valacyclovir); however, in some casesidoxuridine, trifluorotimidine, vidarabine and foscamet are indicated.In topical applications, acyclovir toxicity is particularly observed incases of hypersensitivity. Furthermore, when systemically administeringantiviral drugs, adverse reactions are frequent occurrences. Topicalanti-inflammatory drugs can also be used as adjuvant agents in thetreatment. It should be observed that in the conventional herpestreatment which is under discussion here, the drugs have a syntheticorigin and their basic activity is antimicrobial.

The pertinent literature explains that the manifestations of recurrentlip herpes occur in 20-45% of the population, and that, regardless ofethnic group or geographic region, approximately 70% of over40-year-olds have antibodies against the type 1 HSV virus. Therecurrence frequency among the affected individuals varies from rareepisodes up to 12 recurrences or more per year. After the primaryinfection, which usually occurs in childhood, the virus establishes alatent infection in the trigeminal ganglions. In immunocompetentindividuals, the reactivations represent episodes of limitedreplication, disappearing in 10 days or so, regardless of any treatment.At this stage, however, the release of infecting viral particles occurs,and they are likely to be contagious. The increasing use of topicalantiviral drugs with activity on the DNA polymerase, such as thenucleoside analogs (acyclovir and pencyclovir), has been regarded as areference for comparative studies. Although the reference treatment isgenerally safe, its clinical efficacy is limited, and there is anincreasing concern about the emergence of a viral resistance due to thedisseminated use of such cytostatic drugs, particularly in populationsof immunocompromised individuals. Forecasts derived from mathematicalmodels suggest that the increasing utilization of nucleoside analogs mayraise the prevalence of resistant viral forms from the current 0.3% to1.5-3.0% in the next 50 years. This possibility could represent anexponentially increasing dissemination of resistant viral forms. On theother hand, the topical drug anti-inflammatory activity itself helps todecrease the viral spreading by decreasing the intensity and duration ofthe symptoms of the active stage, in which the infection is likely tooccur.

Among the most recent approaches to the treatment of inflammationscaused by the herpes virus, phytotherapy, also referred to as herbalmedicine, has been increasingly employed. One of the most promisingplants is Uncaria tomentosa, colloquially known as “unha de gato” inBrazil, and, in other countries, as cat's claw, una de gato, paraguayo,garabato, garabato casha, samento, toron, tambor huasca, una huasca, unade gavilan, hawk's claw, saventaro.

The Uncaria tomentosa portions most used for phytotherapic purposes arethe bark, roots and leaves. The traditional methods of manipulation ofthese portions for obtaining their therapeutically active componentsinvolve grinding, coction and extraction by means of solvent substances,with an optional heating.

Uncaria tomentosa belongs to the Rubiaceae family, formed by the mainspecies U. tomentosa and U. guianensis. It has been used for centuriesby Indians and the Amazonian forest populations for treating asthma,inflammations of the urinary tract, postpartum recovery, kidneyinfections, arthritis, rheumatism, gastric ulcers, cancer, and diabetes,among other illnesses. This fact suggests that U. tomentosa contains awide range of therapeutic and prophylactic components. In relativelyrecent years the ethnologist Klaus Keplinger offered a decisivecontribution for the elucidation of the U. tomentosa compound and itspotential strength as a phytotherapic agent, inclusively for thetreatment of cancer and AIDS, according to the patents U.S. Pat. No.4,844,901, U.S. Pat. No. 4,940,725, U.S. Pat. No. 5,302,611, and U.S.Pat. No. 5,723,625. Keplinger's work has been amplified by contributionsfrom other researchers, who have taken ahead the task of elucidating thecomponents' potential phytotherapic activity and determining how theycan be put to use.

The chemical compound of U. tomentosa includes 17 different alkaloids,glycosides of the quinovic acid, tannins, flavonoids, steroid fractions,including sitosterol, sigmasterol and carpesterol, triterpenes and othercompounds (Sentore A, Cataldo A, Iaccarino F, et al. Phytochemnical andbiological research on Uncaria tomentosa L. Boll Soc Ital Biol Sper1989; 65:517-520). The “James Duke's Phytochemnical and Ethnobotanical”database presents a list of 29 chemical constituents present in Uncariatomentosa (Beckstrom-Sternberg S, Duke J, Wain K. Chemicals in: Uncariatomentosa DC (Pedaliaceae). 1994: The Ethnobotany Database, AgriculturalResearch Service). The following active constituents are particularlynotable: the tetracyclic oxindole alkaloids (TOAs), represented by thecompounds rynchophylline, isorynchophylline, corynoxeine, andisocorynoxeine (Keplinger et al., 1999 (Keplinger K, Laus G, Wurm M, etal. Uncaria tomentosa (Willd.) DC-Ethnomedicinal use and newpharmacological, toxicological and botanical results. J Ethnopharmacol1999; 64:23-34); Laus G, Brossiner D, Keplinger K. Alkaloids of PeruvianUncaria tomentosa. Phytochemistry;45(4):855-860), 1997); Wagner H,Kreutzkamp B, Jurcic K. The alkaloids of Uncaria tomentosa and theirphagocytosis-stimulating action [in German]. Planta Med 1985b October;(5):419-23). The most frequently investigated active constituents, whichpresent immunomodulator and anti-inflammatory effects, are thepentacyclic oxindole alkaloids (PDAs). The already characterized POAsare: pteropodine, uncarine C, isopteropodine, uncarine E,speciophylline, uncarine F, Mitraphyllinee, and isoMitraphyllineee(Muhammad et al., 2001a (Muhammad I, Khan I A, Fischer N H, Fronczek FR. Two stereoisomeric pentacyclic oxindole alkaloids from Uncariatomentosa: uncarine C and uncarine E. Acta Cryst 2001a; C57:240-2); Lauset al., 1997; Wagner et al., 1985b; Stuppner H, Sturm S, Konwalinka G.HPLC analysis of the main oxindole alkaloids of Uncaria tomentosa.Chromatographia 1992; 34:597-600).

Uncaria tomentosa has got two chemotypes: (1) the pentacyclic alkaloidstype, and (2) the tetracyclic alkaloids type. The first one, whichcontains pentacyclic oxindole alkaloids (PDAs), is regarded by someresearchers as the most active component of the cat's claw plant andcontains just a few—or even none—tetracyclic oxindole alkaloids (TOAs).The second chemotype contains predominantly TOAs, both with no POAs atall and with a considerable amount of POAs. The TOAs are believed to bePOAs antagonists on what concerns to the POAs' desirable effects, and,therefore, it is important to tell the two chemotypes from one another(Wurm M, Kacani L, Laus G, Keplinger K, Dierich M. Pentacyclic oxindolealkaloids from Uncaria tomentosa induce human endothelial cells torelease a lymphocyte-proliferation-regulating factor. Planta Med 1998;64:701-704).

Thus, the determination of the chemotype is crucially important in theplant's analysis and processing, with the purpose of obtaining apharmaceutical preparation. This is due to the fact that the pentacyclicand tetracyclic alkaloids possess different activity mechanisms, and aspreviously mentioned, they may even be antagonists to each other(Keplinger, K., Laus, G., Wurm, M. et col.: Uncaria tomentosa (Willd.)DC. —ethnomedicinal use and new pharmacological, toxicological andbotanical results. J Ethnopharmacol, 1999, 64: 23-34; Reinhard K. H.:Uncaria tomentosa (Willd.) DC. —Cat's claw, Una de gato oderKatzenkralle. Z. Phytother, 1997, 18: 112-121).

The document FR 2824270 describes a process of preparation of ahydroalcoholic extract from Uncaria tomentosa (Example 1, b1-a), inwhich finely sectioned portions of the plant are subject to reflux, at atemperature of 65.degree. C., for 2 hours, in a 70% ethanol aqueoussolution. This process presents some disadvantages, such as: (i) heatingfavors isomerization and other alterations in the physical-chemicalcharacteristics of the constituents found in the in natura plant, and(ii) the chemical non-characterization and non-standardization of theextract obtained prevents the control of the final product's therapeuticactivity. As a matter of fact, the compound described in the document FR2824270 has got a predominantly cosmetic purpose.

Pharmacological studies have shown that the pentacyclic oxindolealkaloids, active constituents of the herbal extract of the plantUncaria tomentosa (Willd) DC Rubiaceae, present immunomodulatoranti-inflammatory, antioxidant and cytoprotective activities. Thequinovic acid glycosides present in Uncaria tomentosa have been testedin cell cultures (CER and HeLa), showing antiviral and anti-inflammatoryactivity. The mutagenic and antimutagenic potential of Uncaria tomentosapresents antimutagenic activity in photomutagenic systems in vitro andabsence of mutagenic effect in Salmonella typhimurium. Experimentally,Uncaria tomentosa could offer protection against a whole range ofoxidative stresses, including the peroxynitrite, which has been impliedas a mediator in the arthritis inflammation and other chronicinflammatory diseases, as well as against the cytotoxicity induced by UVrays and free radicals. The anti-inflammatory effect of Uncariatomentosa results from its ability of inhibiting the production ofTNF-alfa in vitro and in vivo and, in a smaller extent, of PGE2, both ofthem mediators of the inflammatory processes. The expression of theNF-kappaB transcription factor, which regulates the transcription ofseveral genes involved in the inflammatory process, is reduced in vitroby Uncaria tomentosa extracts. On the other hand, its immunomodulatoreffect has been attributed to the increase in the lymphocites'proliferative ability, the stimulation of the phagocitary activity andthe increase in the IL-1 and IL-6 production. Studies of the preclinicaltoxicity of the Uncaria tomentosa extracts have not shown any toxicityin vitro in concentrations up to 100 mg/ml.

Two tests (uncontrolled; unpublished results) with the extract of U.tomentosa-POA in topical preparations to be used in lesions caused byHerpes simplex and Varicela zoster have been performed, with betteroutcomes and with no adverse side effects (Immodal Pharmaka.Krallendorn® Uncaria tomentosa (Willd.) DC Root Extract: Information forPhysicians and Dispensing Chemists. 3rd revised ed. Volders,Austria:Immodal; 1995. Available on request fromimmodal@volders.netwing.at. Immodal Pharmaka. Radix Uncariae tomentosae(Willd.) DC., pentacyclic chemotype (Krallendorn®): summarized research.Volders, Austria; Immodal. 2002. Immodal Pharmaka. Summary andassessment of clinical examinations of Krallendorn® products. Volders,Austria: Immodal, 1999a, Available on request fromimmodal@volders.netwing.at.; Immodal Pharmaka. Summary and assessmentof: Pharmacodynamical examinations of extracts of Uncaria tomentosa(Willd.) DC. mod. pent. Volders, Austria: Immodal; 1999b).

In Western Europe the U. tomentosa extracts are used in daily doses ofapproximately 20-60 mg of the dry extract. The POAs are poorly solublein water and well soluble in acids and alcohols; therefore, the U.tomentosa extracts are prepared in the form of 50% hydroalcoholictinctures. In Germany and Austria the U. tomentosa extract in the formof a standardized powder is used two or three times a day in doses of20-60 mg. Also in those two countries the preparations made from U.tomentosa roots are used mainly in disorders of the immune system(including allergies and rheumatoid arthritis) and as a supportivetherapy to the treatment of cancer (to alleviate the consequences ofchemotherapy and radiotherapy), as well as an adjuvant in viralinfections with herpes or retroviruses as the HIV (Falkiewicz, B.,ukasiak, J. “Vilcacora [Uncaria tomentosa (Willd.) DC. and Uncariaguianensis (Aublet) Gmell.]—a review of published scientific literature.Case Rep Clin Pract Rev, 2001: 2(4): 305-316).

In the United States market 4 types of Uncaria products arecommercialized by 3 different manufacturers: (1) hydroalcoholic extractfrom U. tomentosa standardized for POAs; (2) aqueous extract from U.tomentosa standardized for CAES; (3) aqueous extract from Uncariaguianensis and (4) a relatively generic cat's claw product (usuallylabeled as UT), made from the plant's bark and roots, both in form ofpowder for capsules and tablets and finely sliced to be used in the formof tea (CAT′S CLAW (VINCARIA) Uncaria tomentosa (Willd.) DC.; Uncariaguianensis (Aubl.) Gmel. [Fam. Rubiaceae]-Overview; available in the Webin (http://www.sunrisewd.com/products/catsclawarticle.htm).

Although processes of extraction of pharmaceutically active components,including the hydroalcoholic extraction of U. tomentosa are alreadyknown, and, in addition to that, products designed for the treatment ofherpes exist in the market, such products do not totally comply with therequisites of a satisfactory relief of the pain associated with theinflammation caused by the herpes virus and of a satisfactorybioavailability (for instance, a sufficient topical absorption) of theactive components of U. tomentosa, especially the POAs.

SUMMARY OF THE INVENTION

The present invention aims at providing a topical phytotherapic compoundfor the treatment of herpes, designed to address the deficiencies of thecompounds known in the art; such compound is to be prepared with anherbal extract from the plant Uncaria tomentosa (Willd) DC Rubiaceae,standardized in Mitraphylline.

Compared to the conventional products, the compound provided by thepresent invention possesses the main advantage of not fostering a viralresistance. While the synthetic or semisynthetic drugs currently in usepresent antimicrobial activity, the present compound exerts animmunomodulator and anti-inflammatory action, increasing the organicresistance itself and not interfering in the viral replication. Comparedto the compounds based on Uncaria known to the technical state for thetreatment of herpes, the compound of the present invention features anefficient action on the pain associated with the inflammation caused byHSV.

In a first concretization of the present invention, a phytotherapiccompound for the treatment of herpes based on Uncaria tomentosa isprovided, characterized by the presence of: (a) a therapeuticallyefficient amount of an Herbal Extract from Uncaria tomentosa (Willd) DCRubiaceae, (b) a pharmaceutically acceptable vehicle, (c) at least onepharmaceutically acceptable excipient, and, (d) optionally,pharmaceutically acceptable adjuvants.

A second concretization of the invention concerns a process ofextraction for obtaining a herbal extract from Uncaria tomentosa,characterized by including the following stages: (a) preparing a finelysliced material from portions of the standardized Uncaria tomentosaplant; (b) mixing the stage (a) material with a 70% ethanol aqueoussolution and performing the turbolysis at room temperature for a periodof time sufficient for extracting the active constituents; (c)separating the liquid phase containing the desired active constituents;(d) filtering the liquid obtained in the stage (c) for removing theremaining solid or semisolid particles; (e) optionally, repeating atleast once the stages (a) through (d) for eliminating all solidmaterials from the desired active constituents, and (0 obtaining theUncaria tomentosa tincture by mixing the fractions resulting from theextractions performed during the stages (a) through (d).

In a third concretization a phytotherapic compound for the treatment ofherpes based on Uncaria tomentosa is provided, characterized by thepresence of: (a) a therapeutically efficient amount of an Herbal Extractfrom Uncaria tomentosa (Willd) DC Rubiaceae, prepared by means of aprocess of extraction, which results in a plant extract from UncariaTomentosa (Willd) DC Rubiaceae, described in the present invention, (b)a pharmaceutically acceptable vehicle, (c) at least one pharmaceuticallyacceptable excipient, and, (d) Optionally, pharmaceutically acceptableadjuvants.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the chromatogram (A) and the spectrum (B) of theMitraphylline standard (t_(r)=12.290), one of the pentacyclic oxindolealkaloids.

FIG. 2 shows the chromatogram (A) and the spectrum (B) of theIsoMitraphyllinee standard (t_(r)=13.382), another pentacyclic oxindolealkaloid. It is worth noting that the eluated peak next to theIsoMitraphyllinee (13.382), in the standard, is the isomeric impurity ofapproximately 15% of Uncarine C, information included in the Chromadexcertificate of analysis.

FIG. 3 shows the chromatogram (A) and the spectrum (B) of the Uncarine Cstandard (t_(r)=13.834), another pentacyclic oxindole alkaloid.

FIG. 4 shows the chromatogram (A) and the spectrum of the Uncarine Estandard (4=16.873), another pentacyclic oxindole alkaloid.

FIG. 5 shows: (A) the chromatogram of the Uncaria Tincture, the activeingredient of the compound in the present invention; and the spectrumsof its constituents: (B) Uncarine F, (C) Mitraphylline, (D)IsoMitraphyllinee, (E) Uncarine C and (F) Uncarine E.

DETAILED DESCRIPTION OF THE INVENTION

For the purpose of the present invention, some definitions are providedbelow:

Herbal extract from Uncaria tomentosa (Willd) DC Rubiaceae—means ahydroalcoholic mixture of Uncaria tomentosa powder, standardized inpentacyclic oxindole alkaloids calculated in Mitraphylline andcharacterized by a spectral profile. The extract's (a) organolepticcharacteristics are: the aspect of a slightly turbid liquid, with theacrid odor characteristic of Uncaria and a reddish brown color, (b)physical-chemical characteristics are: (i) dry residue: 2.95-5.23%, (ii)pH: 5.0-5.5, (iii) density: 0.862-0.982 g/ml, (iv) content of totalpentacyclic oxindole alkaloids, calculated as Mitraphylline: 660μg/g-900 μg/g, and (v) identification by thin layer chromatography withbands in Rfs close to 0.7-0.8 and 0.25-0.3 related to the alkaloids.

POAs-term related to the pentacyclic oxindole alkaloids (PDAs) presentin several portions of the Uncaria tomentosa plant, especially the rootand bark. The POAs include: pteropodine, uncarine C, isopteropodinie,uncarine E, speciophylline, uncarine F, Mitraphyllinee, andisoMitraphyllineee.

As previously mentioned, the constitution of the Uncaria tomentosaextract depends, in a great extent, on the process used. This factderives mainly from the differentiated solubility of the componentspresent in the several portions of the plant, such as the root, bark andleaves, which are distributed over different chemical classes ofcompounds. For instance, the POAs are less soluble in water than theTOAs are.

In the present invention, the herbal extract from Uncaria tomentosa(Willd) DC Rubiaceae is obtained by means of a hydroalcoholic extractionprocess under strictly controlled conditions which ensures thepreservation of the chemical structure and biological activity of thecomponents present in the plant.

In a preferred concretization, the herbal extract from Uncaria tomentosa(Willd) DC Rubiaceae is obtained by means of an extraction process whichincludes the following stages: (a) preparing a finely sliced materialfrom portions of the standardized Uncaria tomentosa plant; (b) mixingthe stage (a) material with a 70% ethanol aqueous solution andperforming the turbolysis at room temperature for a period of timesufficient for extracting the active constituents; (c) separating theliquid phase containing the desired active constituents; (d) filteringthe liquid obtained in the stage (c) for removing the remaining solid orsemisolid particles; (e) optionally, repeating at least once the stages(a) through (d) for eliminating all solid materials from the desiredactive constituents, and (f) obtaining the Uncaria tomentosa tincture bymixing the fractions resulting from the extractions performed during thestages (a) through (d). This process ensures the preservation of thephysical-chemical characteristics of the phytocomplex, minimizing theoccurrence of possible alterations caused by more severe conditions,such as heating, which frequently results in the formation of isomersand the consequent decrease in the extract's phytotherapic activity.

The finely sliced material utilized in the stage (a) of the processshould preferably be in the form a powder obtained by the fragmentationof the plant's portions, preferentially the root, bark and/or leaves. Onthe stage (b) the Uncaria tomentosa material, finely sliced, is mixedwith a 70% ethanol aqueous solution (with the pH corrected to 4.5 by theaddition of organic acid) and subject to agitation, by turbolysis, for apreferential period of time of about 1 hour. The separation of theliquid phase in the stage (c) is preferably performed by centrifugationat, for instance, 60 Hz. The filtration, in the stage (d), is performedby an appropriate filtering system, such as depth filtration or filterpress.

The stages (a) through (d) should preferably be repeated several timesto ensure the maximal removal of the desired constituents present in thein natura plant. More preferentially, at least two extractions should beperformed. More preferably yet, at least three extractions should bemade.

The extract obtained by such process is a reddish liquid which containsan amount of total alkaloids, calculated as Mitraphylline, of about 660μg-900 μg.

FIGS. 5A and B shows the qualitative analysis of the pentacyclicoxindole alkaloids included in the Uncaria tincture used in the mostpreferred compound of the present invention, here denominated HerbalExtract from Uncaria tomentosa (Willd) DC Rubiaceae. In the FIG. 5 (A)the tincture's chromatogram is presented. In the FIGS. 5 (B) through 5(F) the spectrums of the tincture's constituents are presented: uncarineF, Mitraphyllinee, isoMitraphyllineee, uncarine C and uncarine E,respectively. The analysis has been performed in a High EfficiencyLiquid Chromatograph assembled with a Diode Arrangement Detector (DAD).

Two parameters have been taken into consideration for the execution ofthe qualitative analysis of the Uncaria tincture's alkaloids:

Comparison of the holding times of the pure standards of the alkaloidsMitraphyllinee, isoMitraphyllineee, uncarine C and uncarine E with therespective eluated peaks during the course of the Uncaria tincture.

Spectral Qualification of every Oxindole Alkaloid present in the Uncariatincture's chromatogram.

For comparison purposes, the FIGS. 1 through 4 illustrate thechromatograms and spectrums of the standards of: Mitraphyllinee,IsoMitraphyllineee, Uncarine C and Uncarine E, respectively. Thechromatogram of the Mitraphyllinee standard shows the eluated peak in12.290 (FIG. 1A), the IsoMitraphyllineee chromatogram in 13.382 (FIG. 2A), the Uncarine C chromatogram has this compound's peak in 13.834 (FIG.3 A), the Uncarine E chromatogram shows the peak in 16.873 (FIG. 4 A).

Compared to what is observed in the Uncaria tincture's chromatogram, thealkaloids' holding times are shown to be: Mitraphylline: 12.251;IsoMitraphyllinee: 13.370; Uncarine C, 13.833; Uncarine E: 16.856. Thecloseness between the holding times is strongly indicative that thecompounds are the same.

In addition to the holding times comparison between the alkaloidsstandards and the eluated peaks in the tincture's analysis, thecomparison by similarity of the spectral profiles of the oxindolealkaloids in the standards and in the sample has been performed.

Such comparison has shown a great similarity between the spectrums ofthe standards and of the eluated compounds with the same holding time inthe tincture. Therefore, a reasonably reliable conclusion can be madethat the alkaloids present in the Uncaria tincture are the standardsinjected in the analysis.

Finally, the analysis of the purity factor of the peaks and of theasymmetry factor of the alkaloids' peaks in the tincture shows theirpurity and resolution.

The compound of the present invention is prepared by the mixture of theactive ingredient herbal extract from Uncaria tomentosa (Willd) DCRubiaceae with a pharmaceutically acceptable vehicle, resulting in atopical application product preferentially in the form of a cream gel.

The compound of the present invention, preferably in the form of a creamgel, contains one or more pharmaceutical excipients or vehicles. Suchexcipients or vehicles are selected from the substances known in thetechnical state and usually utilized for that purpose. At least one ofthe excipients or vehicles is a solvent of the used active ingredient,selected from the group which includes water; alcohols with a lowmolecular weight, preferably alcohols C₁ to C₅, more preferably ethanol,2-propanol, isopropanol, t-butanol; ethers, such as the MTBE; ketones,such as acetone, methyl ethyl ketone. The compound of the inventioncontains as well: humectants, such as glycerol; glycols, such asethylene glycol, propylene glycol; emulsifiers, such as the alcohols C₁to C₅, optionally polyhydric partially esterified with long-chain fattyacids C₁₂ to C₂₄, such as glycerol monostearate, isopropyl myristate,sugar alcohols fatty acid ester, such as the sorbitan fatty acidmonoester, polyoxyalkilate derivates of those compounds,polyetoxyethylene fatty acid ester, cholesterol, cetyl estearyl alcohol,cotton wax alcohols and synthetic tensoactive agents with a low HLBvalue; viscosity donors or rheology modifiers such as carbopol, or otherpolymers or synthetic or natural gums; low viscosity paraffins,emollient esters and alcohols, triglycerides, lipophilic substances suchas isopropyl myristate or isopropyl palmnitate; pH regulators such asTEA, carbonates or phosphates; quelant agents such as EDTA and itssalts, as well as preservatives, such as methylparaben andpropylparaben; emollient agents such as oils or waxes of vegetal origin,such as the musk rose oil; antioxidants as BHT or other antioxidantmixtures.

Furthermore, the compound in form of gel of the present invention maycontain substances with UV filter properties, pigments, vitamins andother adjuvants frequently used in compounds for topical application.

In a preferred concretization, the compound of the present invention isin the form of a hydrophilic cream gel, meaning it has an elevated watercontent (80-90%).

In an especially preferred concretization, the topical phytotherapiccompound for the treatment of herpes presents the following composition:TABLE-US-00001 Herbal extract from Uncaria tomentosa 4.25-5.75% (Willd)DC Rubiaceae (active principle) Emulsifying compound (excipient)3.4-4.6% Sorbitol esters derived from Colza Oil (Brassicacampestris)—CAS 91081-14-0 Copolymer of the acryloylmethyltauratesulfonic acid and neutralized vinylpirrolidone—CAS 75-65-0 CitricAcid—CAS 77-92-9 Isopropyl palmitate—CAS 142-91-6 TetradibutylPentaerythrityl Hydroxyhydrocinnamate 0.0425-0.0575% (excipient)—CAS6683-19-8 Disodium EDTA (excipient)—CAS 139-33-3 0.085-0.115%Methylparaben (excipients)—CAS 99-79-3 0.17-0.23% Propylparaben(excipients)—CAS 94-13-3 1.1275-0.1725% Glycerin (excipients)—CAS56-81-5 2.55-3.45% Rosa Aff. Rubiginosa oil (excipient) 2.125-2.875%Deionized water (vehicle) q.s. 100%.

This topical phytotherapic compound for the treatment of herpes resultsin a semi viscous cream gel product with a glossy aspect, salmoncolored, with pH in a 4.8-5.8 range, and with dosing of total oxindolealkaloids calculated in Mitraphylline of 28-38 μg/g.

In the tests performed with the especially preferred compound of thepresent invention, the activities of the topical phytotherapic activesubstance for the treatment of herpes in nociception and inflammationmodels were studied; it was observed that, in the test offormalin-induced pain, the compound presented a significantantinoceptive activity at the second stage of the pain, with a 41.7%decrease in the pain threshold. Said composition has also presented asignificant (36%) reduction of the oedema.

Such outcomes have confirmed that the compound of the present inventionexerts a surprising analgesic effect on pain of inflammatory origin dueto the release of inflammatory mediators such as histamine, serotonin,bradykinin and prostaglandins. In the characterization of itsantioedematogenic activity, by means of the test of thecaragenine-induced paw oedema, the compound caused a 11% decrease insuch oedematogenic response, confirming its ability of oedema reduction.The compound of the invention has presented no significant antinoceptiveeffect in the test of capsaicin-induced neurogenic pain and in the TailFlick test.

The compound of the present invention has confirmed its significantaction in inhibiting the pain of inflammatory origin, with ananti-inflammatory efficiency of 87.2% compared to the 73.9% of thestandard drugs known of the technical state.

The preferred compound is illustrative of the present invention, and itis worth noting that the components are combined and the amounts arerepresented in a percentage by weight, based on the total weight of thecompound which contains the topical phytotherapic extract.

It is emphasized that the invention is not restricted to the preferredcompound, and the invention should be understood in its ample scope.Many modifications and other representations of the invention may cometo the mind of those skilled in the art, with the benefit of theinformation included in the description. Moreover, it should beunderstood that the present invention is not limited to the specificallydisclosed content, and that eventual alterations should be taken asincluded within the scope of what is claimed ahead. Although specificterms have been utilized, they were used in a generic and descriptiveway and not with a restrictive purpose.

1. A topical phytotherapic compound for the treatment of herpes, the compound comprising: (a) a therapeutically effective amount of a herbal extract from Uncaria tomentosa (Willd) DC Rubiaceae; (b) a pharmaceutically acceptable vehicle, and (c) at least one pharmaceutically acceptable excipient.
 2. The topical phytotherapic compound according to claim 1, further comprising a pharmaceutically acceptable adjuvant.
 3. The topical phytotherapic compound according to claim 1, wherein the herbal extract from Uncaria tomentosa (Willd) DC Rubiaceae: (a) has an appearance of a slightly turbid liquid; (b) has an acrid odor characteristic of Uncaria tomentosa; (c) has a reddish brown color; (d) has a dry residue of from 2.95% to 5.23%; (e) has a pH of from 5.0 to 5.5; (f) has a density of from 0.862 g/ml to 0.982 g/ml; (g) has a content of total pentacyclic oxindole alkaloids, calculated as mitraphyline, from about 660 μg/g to about 900 μg/g; (h) identification by thin layer chromatography with bands in RFs of about 0.7 to 0.8 and about 0.25 to 0.3 related to the alkoids, and (i) identification by HPLC chromatogram as described in FIG. 5(A).
 4. The topical phytotherapic compound according to claim 1, wherein the therapeutically effective amount of the herbal extract from Uncaria tomentosa (Willd) DC Rubiaceae is from about 4.25% to 5.75%.
 5. The topical phytotherapic compound according to claim 1, wherein the at least one pharmaceutically acceptable vehicle is selected from the group consisting of: water; alcohols with molecular low weight; ethers; and ketones.
 6. The topical phytotherapic compound according to claim 5, wherein the alcohols with molecular low weight of the at least one pharmaceutically acceptable vehicle is selected from the group consisting of: alcohols C₁ to C₅.
 7. The topical phytotherapic compound according to claim 5, wherein the alcohols with molecular low weight of the at least one pharmaceutically acceptable vehicle is selected from the group consisting of: ethanol, 2-propanol, isopropanol, and t-butanol.
 8. The topical phytotherapic compound according to claim 5, wherein the ether is MTBE.
 9. The topical phytotherapic compound according to claim 5, wherein the ketone is selected from the group consisting of: acetone and methyl ethyl ketone.
 10. The topical phytotherapic compound according to claim 1, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of: humectants; glycols; emulsifiers; synthetic tensoactives with a low HLB value solubilizing agents, stable viscosity agents; low viscosity paraffins; emollient esters and alcohols; triglycerides; lipophilic substances; pH regulators; quelant agents; preservatives; emollient agents; and antioxidant agents.
 11. The topical phytotherapic compound according to claim 10, wherein the humectant is a glycerol.
 12. The topical phytotherapic compound according to claim 10, wherein the glycol is selected from the group consisting of: ethylene glycol and propylene glycol.
 13. The topical phytotherapic compound according to claim 10, wherein the emulsifier is selected from the group consisting of: alcohols C₁ to C₅; polyhydric partially esterified with long-chain fatty acids C₁₂ to C₂₄, selected from the group consisting of: glycerol monostearate; isopropyl myristate; sugar alcohols fatty acid ester selected from the group consisting of: sorbitan fatty acid monoester, polyoxyalkilate derivates of those compounds, polyetoxyethylene fatty acid ester, cholesterol, cetyl estearyl alcohol, cotton wax alcohols; and synthetic tensoactive agents with a low HLB value.
 14. The topical phytotherapic compound according to claim 10, wherein the stable viscosity agents is selected from the group consisting of: carbopol; others polymers with similar properties and for the same purpose; synthetic gums with similar properties and for the same purpose; and natural gums with similar properties and for the same purpose.
 15. The topical phytotherapic compound according to claim 10, wherein the lipophilic substance is selected from the group consisting of: isopropyl myristate and isopropyl palmitate.
 16. The topical phytotherapic compound according to claim 10, wherein the pH regulator is selected from a group consisting of: TEA, carbonates, and phosphates.
 17. The topical phytotherapic compound according to claim 10, wherein the quelant agent is EDTA or its salts.
 18. The topical phytotherapic compound according to claim 10, wherein the preservative is selected from the group consisting of: methylparaben and propylparaben.
 19. The topical phytotherapic compound according to claim 10, wherein the emollient agent is selected from the group consisting of: Rosa Aff. Rubiginosa oil; similar oils of vegetal origin; and similar waxes of vegetal origin.
 20. The topical phytotherapic compound according to claim 10, wherein the antioxidant agent is BHT or other suitable antioxidant mixtures.
 21. The topical phytotherapic compound according to claim 1, the compound comprising: (i) from about 4.25% to about 5.75% of herbal extract from Uncaria tomentosa (Willd) DC Rubiaceae; (ii) from 3.4% to 4.6% of an emulsifying agent selected from the group consisting of: sorbitol esters derived from colza oil (Brassica campestris); copolymer of acryloylmethyltaurate sulfonic acid; neutralized vinylpyrrolidone; citric acid; and isopropyl palmitate; (iii) from 0.0425% to 0.0575% of tetradibutyl pentaerythrityl hydroxyhydrocinnamate; (iv) from 0.085% to 0.115% of dissodic EDTA; (v) from 0.17% to 0.23% of methylparaben; (vi) from 1.1275% to 0.1725% of propylparaben; (vii) from 2.55% to 3.45% of glycerin; (viii) from 2.125% to 2.875% of Rosa Aff. Rubiginosa oil, and (ix) deionized water q.s. 100%.
 22. The topical phytotherapic compound according to claim 1, wherein the compound is in the form of a cream gel.
 23. The topical phytotherapic compound according to claim 1, wherein the compound is in the form of a semi viscous cream gel with a glossy aspect, having a pH from 4.8 to 5.8, and a total oxindolic alkaloid dosage calculated in mitraphyllin of from about 28 μg/g to 38 μg/g.
 24. The topical phytotherapic compound according to claim 23, wherein the compound in the form of a semi viscous cream gel is salmon colored. 